Influence of antimonite, selenite, and mercury on the toxicity of arsenite in primary rat hepatocytes

The long-term toxicity of arsenic (As) as a result of exposure to contaminated drinking water might be modified by coinciding exposures to elements like selenium, antimony, or mercury. In this study the influence of tetravalent selenite, trivalent antimonite, and divalent mercury was investigated in vitro using cultured primary rat hepatocytes. The cell vitality was assessed in the 3-[4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide] (MTT), assay with concurrent exposures of the cells to up to 50 mu M sodium arsenite(III) and a potential modifier [50 mu M sodium(IV) selenite,10 mu M antimony(III) chloride, 25 mu M mercuric(II) chloride], which indicated an additive increase in the combined cytotoxicity. Sodium arsenite was tested for genotoxicity in the micronucleus test in a concentration range of 0.25 up to 7.5 mu M. In this range, the MTT conversion was at least 80%, indicating high cell viability. A dose-dependent induction of micronuclei was observed. The lowest concentration causing a significantly elevated frequency of micronuclei was 1 mu M As (p < 0.05). A significant influence (i.e., reduction of the combined genotoxicity as a result of the presence of a potential modifier) was only observed for 10 and 25 PM antimony chloride (p < 0.05, Fisher's exact test). The metabolic methylation of arsenite was not affected by concurrent incubation with any of the potential modifiers

Genotoxic and epigenetic mechanisms in arsenic carcinogenicity

Arsenic is a human carcinogen with weak mutagenic properties that induces tumors through mechanisms not yet completely understood. People worldwide are exposed to arsenic-contaminated drinking water, and epidemiological studies showed a high percentage of lung, bladder, liver, and kidney cancer in these populations. Several mechanisms by which arsenical compounds induce tumorigenesis were proposed including genotoxic damage and chromosomal abnormalities. Over the past decade, a growing body of evidence indicated that epigenetic modifications have a role in arsenic-inducing adverse effects on human health. The main epigenetic mechanisms are DNA methylation in gene promoter regions that regulate gene expression, histone tail modifications that regulate the accessibility of transcriptional machinery to genes, and microRNA activity (noncoding RNA able to modulate mRNA translation). The "double capacity" of arsenic to induce mutations and epimutations could be the main cause of arsenic-induced carcinogenesis. The aim of this review is to better clarify the mechanisms of the initiation and/or the promotion of arsenic-induced carcinogenesis in order to understand the best way to perform an early diagnosis and a prompt prevention that is the key point for protecting arsenic-exposed population. Studies on arsenic-exposed population should be designed in order to examine more comprehensively the presence and consequences of these genetic/epigenetic alterations. © 2014 Springer-Verlag